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Chemical genomics reveals histone deacetylases are required for core regulatory transcription

Author

Listed:
  • Berkley E. Gryder

    (NIH)

  • Lei Wu

    (Dana-Farber Cancer Institute)

  • Girma M. Woldemichael

    (Frederick National Laboratory for Cancer Research)

  • Silvia Pomella

    (NIH
    Ospedale Pediatrico Bambino Gesu’ Research Institute)

  • Taylor R. Quinn

    (University of Notre Dame)

  • Paul M. C. Park

    (Dana-Farber Cancer Institute)

  • Abigail Cleveland

    (NIH)

  • Benjamin Z. Stanton

    (NIH)

  • Young Song

    (NIH)

  • Rossella Rota

    (Ospedale Pediatrico Bambino Gesu’ Research Institute)

  • Olaf Wiest

    (University of Notre Dame)

  • Marielle E. Yohe

    (NIH)

  • Jack F. Shern

    (NIH)

  • Jun Qi

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Javed Khan

    (NIH)

Abstract

Identity determining transcription factors (TFs), or core regulatory (CR) TFs, are governed by cell-type specific super enhancers (SEs). Drugs to selectively inhibit CR circuitry are of high interest for cancer treatment. In alveolar rhabdomyosarcoma, PAX3-FOXO1 activates SEs to induce the expression of other CR TFs, providing a model system for studying cancer cell addiction to CR transcription. Using chemical genetics, the systematic screening of chemical matter for a biological outcome, here we report on a screen for epigenetic chemical probes able to distinguish between SE-driven transcription and constitutive transcription. We find that chemical probes along the acetylation-axis, and not the methylation-axis, selectively disrupt CR transcription. Additionally, we find that histone deacetylases (HDACs) are essential for CR TF transcription. We further dissect the contribution of HDAC isoforms using selective inhibitors, including the newly developed selective HDAC3 inhibitor LW3. We show HDAC1/2/3 are the co-essential isoforms that when co-inhibited halt CR transcription, making CR TF sites hyper-accessible and disrupting chromatin looping.

Suggested Citation

  • Berkley E. Gryder & Lei Wu & Girma M. Woldemichael & Silvia Pomella & Taylor R. Quinn & Paul M. C. Park & Abigail Cleveland & Benjamin Z. Stanton & Young Song & Rossella Rota & Olaf Wiest & Marielle E, 2019. "Chemical genomics reveals histone deacetylases are required for core regulatory transcription," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11046-7
    DOI: 10.1038/s41467-019-11046-7
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    Cited by:

    1. Ziad Ibrahim & Tao Wang & Olivier Destaing & Nicola Salvi & Naghmeh Hoghoughi & Clovis Chabert & Alexandra Rusu & Jinjun Gao & Leonardo Feletto & Nicolas Reynoird & Thomas Schalch & Yingming Zhao & Ma, 2022. "Structural insights into p300 regulation and acetylation-dependent genome organisation," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    2. Yong Yean Kim & Berkley E. Gryder & Ranuka Sinniah & Megan L. Peach & Jack F. Shern & Abdalla Abdelmaksoud & Silvia Pomella & Girma M. Woldemichael & Benjamin Z. Stanton & David Milewski & Joseph J. B, 2024. "KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Dominik Laubscher & Berkley E. Gryder & Benjamin D. Sunkel & Thorkell Andresson & Marco Wachtel & Sudipto Das & Bernd Roschitzki & Witold Wolski & Xiaoli S. Wu & Hsien-Chao Chou & Young K. Song & Chao, 2021. "BAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

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